This invention relates to a process for preparing 1,4-dihydropyridine compounds. Compounds having 1,4-dihydropyridine structure are widely used in pharmaceutical industry. The compounds have been used, for example, in treating or preventing diseases such as cardiovascular disease and inflammation diseases.
Nifedipine and amlodipine are well-known 1,4-dihydropyridine compounds as calcium channel blockers.
Recently, it has been discovered that certain 1,4-dihydropyridine compounds possess bradykinin antagonistic activity. For example, PCT international patent publications WO 96/06082 and WO97/30048, and U.S. Pat. No. 5,861,402 disclose 1,4-dihydropyridine compounds possessing bradykinin antagonistic activity which are thus useful in the treatment of diseases or symptoms including an inflammation disease, a cardiovascular disease, and a pain producing trauma. These bradykinin-antagonist compounds are characterized by having, at its 2-position with a substituent comprising such as carbonyl, ester, amide or imide moiety.
Various 1,4-dihydropyridine preparation processes have been disclosed. For example, Hantzsch synthesis has been widely used as a 1,4-dihydro-2,6-dimethyl-pyridine preparation process. The process can be carried out by condensation of two moles of a xcex2-dicarbonate with one mole of an aldehyde in the presence of ammonia. J. B. Sainani reported synthesis of a 1,4-dihydro-2,6-dimethyl-pyridine compound which has asymmetrical substituents at its 3- and 5-positions (Org. Chem. Incl. Med. Chem. (1994), 33b (6),573-575).
The present invention provides a process for preparing 1,4-dihydropyridine compounds which comprises the steps of (a) contacting an enamine compound having structure of 
and a compound having a structure of 
in the presence of a base; and (b) treating the reaction mixture thus obtained in the presence of an acid or a combination of acids.
The present invention also provides a process for preparing a compound of formula (I): 
wherein
R1 is selected from hydrogen and (C1-C4)alkyl;
R2 is selected from nitrile; xe2x80x94SO3H; xe2x80x94SO2xe2x80x94(C1-C6)alkyl; xe2x80x94SOxe2x80x94(C1-C6)alkyl; xe2x80x94PO[O(C1-C6)alkyl]; xe2x80x94C(xe2x95x90O)xe2x80x94R7, wherein R7 is selected from hydroxy or its salt, (C1-C6)alkyl-Oxe2x80x94, amino, (C1-C6)alkyl-NHxe2x80x94 and di[(C1-C6)alkyl]-Nxe2x80x94;
R3 and R5 are independently selected from nitrile and (C1-C5)alkoxy-C(xe2x95x90O)xe2x80x94;
R4 is an unsubstituted or a mono-, di-, tri-, tetra- or penta-substituted phenyl wherein the substituents are independently selected from halo; (C1-C4)alkyl optionally substituted with one to three halo; (C1-C4)alkoxy optionally substituted with one to three halo; nitro; amino; mono(C1-C4)alkylamino and di[(C1-C4)alkyl]amino;
R6 is selected from hydrogen; (C1-C10)alkyl; phenyl optionally substituted with one to two substituents independently selected from halo, (C1-C4)alkyl, tri-halo(C1-C4)alkyl and (C1-C4)alkoxy; and a 4- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms or heteroatom containing moieties independently selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 and xe2x80x94N[(C1-C4)alkyl]-, wherein said heterocyclic ring is saturated, partially-saturated or aromatic, and said heterocyclic ring is optionally substituted with one halo or (C1-C4)alkyl; and
Y is selected from a covalent bond, methylene, oxygen and sulfur; the process comprising the steps of
(a) addition reaction of an enamine compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein R1, R2, R3, R4, R5, R6 and Y are as defined above in the presence of a base under reaction conditions sufficient for coupling the compounds; and
(b) cyclization of the resulting compound in step (a) in the presence of an acid catalyst selected from a protonic acid, and a combination of a protonic acid and a non-protonic Lewis acid.
In the above described processes, compounds of formula (I) or (II) wherein R2 is a salt of carboxyl group (i.e., R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R7 wherein R7 is a salt of hydroxy) are inorganic or organic salts of the carboxylic acid. Those salts are formed with a cation such as alkali or akaline earth metal (e.g., sodium, potassium, calcium, and magnesium), hydroxide or alkoxide in water or an appropriate organic solvent such as ethanol, isopropyl alcohol or mixture thereof.
According to the present invention, in general, desired 1,4-dihydropyridine compounds can be prepared under mild conditions, in a one-pot synthesis and high-yield.
In the above process, preferred substrates of formula (II) and resulting compounds of formula (I) are those compounds of each formula wherein R1 is hydrogen.
The term xe2x80x9c(C1-C4)alkylxe2x80x9d, as used herein, unless otherwise indicated, means a straight or branched saturated monovalent hydrocarbon radical selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
The term xe2x80x9c(C1-C4)alkoxyxe2x80x9d, as used herein, unless otherwise indicated, means a straight or branched (C1-C4)alkyl-O radical selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy.
The term xe2x80x9cheterocyclic ringxe2x80x9d, as used herein, unless other wise indicated, means a monocyclic or bicyclic hydrocarbon group which has one or more hetero atoms in the ring, preferably has 6 to 9 carbon atoms and 1 to 4 hetero atoms or independently selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N[(C1-C4)alkyl]-, wherein said heterocyclic is saturated, partially-saturated or aromatic. Examples of those groups include, but not limited to piperidino, morpholino, thiamorphorino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl.
The term xe2x80x9chaloxe2x80x9d, as used herein, refers to F, Cl, Br or I, preferably F or Cl.
Preferred bases used in reaction step (a) of this invention include bases capable of promoting a Michael-type reaction.
Preferred combination of xe2x80x9cbase in step (a)xe2x80x9d and xe2x80x9cacid catalyst in step (b)xe2x80x9d may be xe2x80x9ca magnesium (II) base in step (a)xe2x80x9d and xe2x80x9ca protonic acid in step (b)xe2x80x9d.
Preferably, an amount of the base is equal or more than 1 equivalent.
Other preferred combination of xe2x80x9cbase in step (a)xe2x80x9d and xe2x80x9cacid catalyst in step (b)xe2x80x9d may be xe2x80x9cbases other than magnesium (II) bases (e.g., alkyl-magnesium-halides, halo-magnesium-alkoxides and magnesium-dialkoxides) which are capable of promoting a Michael-type reaction in step (a)xe2x80x9d and xe2x80x9ca combination of a protonic acid and a non-protonic Lewis acidxe2x80x9d. Any non-protonic Lewis acids known to those skilled in the art such as metal halides, metal triflates (i.e., metal trifluoromethanesulfonate) or the like may be used in step (b). Examples of the Lewis acid include magnesium bromide, magnesium chloride, zinc bromide, zinc chloride, zinc iodide, tin(IV) chloride, titanium(IV) chloride, aluminium trichloride, ethylaluminum dichloride, diethylaluminum chloride, boron trifluoride, copper(II) triflate, scandium(III) triflate, lanthanum triflate, ytterbium triflate, lanthanum chloride, cerium(III) chloride and iron(III) chloride. Preferred individual Lewis acids include magnesium bromide and its ether complex such as magnesium bromide diethyl etherate, magnesium chloride and its ether complex such as magnesium chloride diethyl etharate, zinc chloride, zinc bromide and scandium(III) triflate. Among the Lewis acids, preferred ones include magnesium (II) salts such as magnesium halides, magnesium bromides and their ether complexes such as magnesium bromide diethyl etherate. Another preferred ones include magnesium (II) salts such as a magnesium sulfate, magnesium acetate, halomagnesiumacetate and halomagnesium sulfate.
Non-protonic Lewis acid such as MgCl2 can be added in the step (a) in advance.
When the starting compounds contain Lewis basic atom(s) such as N and O, an amount of the Lewis acid added may be increased for the success of step (b).
Preferably, a process of this invention may be carried out under reaction conditions wherein reaction step (a) is carried out in a reaction inert solvent at a temperature in the range from xe2x88x92150xc2x0 C. to the reflux temperature of the reaction mixture for 3 minutes to 2 days; and reaction step (b) is carried out in a reaction inert solvent at a temperature in the range from xe2x88x92150xc2x0 C. to the reflux temperature of the reaction mixture for 1 second to 5 days.
More preferably, a process of this invention may be carried out under reaction conditions wherein the reaction step (a) is carried out in a reaction inert solvent at a temperature in the range from xe2x88x9240xc2x0 to 80xc2x0 C. for 1 minute to 40 hours; and the reaction step (b) is carried out in a reaction inert solvent at a temperature in the range from xe2x88x9240xc2x0 to 80xc2x0 C. for 1 minute to 5 days.
Preferred bases used in reaction step (a) of this invention include (C1-C4)alkyllithiums, halomagnesium(C1-C4)alkoxide, (C1-C6)alkylmagnesiumhalides, metalhydrides, metal(C1-C3)alkoxides, metal-n-butoxide, metal-sec-butoxide, metal-tert-butoxide, metalcarbonate and metalfluoride.
Preferred acids used in reaction step (b) of this invention include hydrochloric acid, toluene (p-, m- or o-toluene) sulfonic acid, phosphoric acid, sulfuric acid, nitric acid and (C1-C6)alkanoic acid.
Preferred process of this invention include a compound of formula (I):
wherein
R1 is selected from hydrogen, methyl and ethyl;
R2 is selected from xe2x80x94C(xe2x95x90O)xe2x80x94R7, wherein R7 is selected from hydroxy or its salt, (C1-C6)alkyl-Oxe2x80x94, amino, (C1-C6)alkyl-NHxe2x80x94 and di[(C1-C6)alkyl]-Nxe2x80x94;
R3 and R5 are independently (C1-C3)alkoxy-C(xe2x95x90O)xe2x80x94;
R4 is di-substituted phenyl wherein the substituents are independently selected from halo, (C1-C4)alkyl optionally substituted with one to two halo, and nitro;
R6 is selected from hydrogen; (C1-C5-)alkyl; phenyl optionally substituted with one to two substituents independently selected from halo, (C1-C4)alkyl, CF3 and (C1-C4)alkoxy; and a 4- to 10-membered heterocyclic ring selected from piperidino, morpholino, thiamorphorino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl, and said heterocyclic ring being optionally substituted with one halo or (C1-C4)alkyl; and
Y is selected from a covalent bond, methylene, oxygen and sulfur.
Preferred process of this invention include a compound of formula (I):
wherein
R1 is hydrogen; R2 is COOH, COOCH3 or COOC2H5;
R3 and R5 are independently COOH, COOCH3 or COOC2H5;
R4 is a mono- or di-substituted phenyl wherein substituents are independently selected from fluoro, chloro and nitro;
R6 is selected from hydrogen; (C1-C3)alkyl; phenyl optionally substituted with one to two substituents independently selected from halo, (C1-C3)alkyl, CF3 and (C1-C3)alkoxy; and a 4- to 10-membered heterocyclic ring selected from piperidino, morpholino, thiamorphorino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl, and said heterocyclic ring being optionally substituted with one halo or (C1-C3)alkyl; and
Y is a covalent bond or methylene.
The following reaction schemes and discussion illustrate the preparation process of the present invention for preparing a compound of formula (I). Unless otherwise indicated, R1 through R8, Y, and p, q and r in the reaction schemes and discussion that follow are defined above. In the each reaction described below, unless otherwise indicated, the reaction pressure is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere). Also, unless otherwise indicated, the reactions run at about room temperature (i.e., from about 20xc2x0 to 25xc2x0 C.).
Compounds of formula (I) may be prepared by a process of this invention according to Scheme 1. 
Scheme 1 exemplifies a process of this invention for preparing a compound of formula (I) comprising step (a): addition of an enamine compound of formula (II) to an alkylene compound of formula (III) followed by step (b) acid catalyzed cyclization reaction of the resulting compound in step (a).
The former addition step (a) may be carried out under conditions applied to nucleophilic addition reactions using a suitable base in a reaction inert solvent. More preferably, the reaction may be carried out under conditions commonly used in Michael-type addition. Preferred bases for this reaction are those used in Michael-type reactions. Examples of the preferred bases include alkylmagnesium halides known as Grignard reagents and halomagnesium alkoxides. More preferred bases include (C1-C6)alkylmagnesium bromide and tert-butoxy-magnesium bromide. Preferred solvents used in this reaction include (C1-C4)alkanol, tetrahydrofuran (THF), diethyl ether, dioxane, hexane, toluene, 1,2-dimethoxy ethane (DME) and the like. This reaction may be carried out at a temperature from about xe2x88x92150xc2x0 C. to reflux, preferably from about xe2x88x92100xc2x0 to 100xc2x0 C. In view of convenience, this reaction may be carried out at about room temperature using, for example, halomagnesium(C1-C4)alkoxides, (C1-C6)alkylmagnesiumhalides, metalhydrides, metal(C1-C3)alkoxides, magnesium-di[(C1-C3)alkoxides], metal-n-butoxide, metal-sec-butoxide, metal-tert-butoxide, a metalcarbonate such as K2CO3, or metalamide such as R2Nxe2x80x94M wherein R is C1-4 alkyl or xe2x80x94Si(C1-3 alkyl)3; and M is Li, Na, Mg or K (Preferably, halomagnesium(C1-C4)alkoxide or (C1-C6)alkylmagnesiumhalides). In case of the base is K2CO3, the reaction is effectively run in THF. In case of the base is CsF or KF, the reaction is effectively run in THF or methanol (MeOH) at an elevated temperature such as at about 60xc2x0 C. In case of using butyllithium (BuLi), the reaction is effectively run in THF at from about xe2x88x9278xc2x0 C. to about xe2x88x9230xc2x0 C. In case of using halomagnesium(C1-C4)alkoxides or (C1-C6)alkylmagnesiumhalides, a preferred solvent is THF. Suitable reaction time ranges from about 3 minutes to about 2 days, preferably from about 30 minutes to about 40 hours.
The subsequent cyclization process step (b) may be carried out in the presence of a protonic acid. Suitable protonic acids include (C1-C6)alkanoic acid such as acetic acid, hydrochloric acid (HCl) and sulfonic acids such as p-toluenesulfonic acid. It is preferred to add a non-protonic Lewis acid to the reaction mixture in combination with the protonic acid, when the base used in Step (a) is other than magnesium (II) bases. This reaction may be carried out at a temperature from about xe2x88x92150xc2x0 C. to reflux, preferably from about xe2x88x92100xc2x0 to 100xc2x0 C. The reaction time ranges from about 1 second to 5 days, preferably 5 minutes to 20 houres.
Generally, those reactions illustrated in Scheme 1 may be carried out at about xe2x88x9278xc2x0 C. using dry-ice/acetone or dry-ice/methanol, about 0xc2x0 C. using an ice-bath, room temperature or 100xc2x0 C. preferably at about 0xc2x0 C. or about room temperature.
The reaction steps (a) and (b) are performed in the same reaction vessel under mild conditions with high-yield.
An enamine compound of formula (II) may be prepared according to procedures known to those skilled in the art, such as those illustrated in Scheme 2. 
Typically, a beta-keto ester compound of formula (IV) may be transformed to a compound of formula (II) wherein R2 and R3 are defined as above. This reduction may be carried out in a reaction inert solvent resolving ammonia gas at a temperature in the range of from about 0xc2x0 to 60xc2x0 C. Suitable reaction inert solvents include lower, alkanols such as methanol and ethanol. Alternatively, an ammonia gas containing solution given above may be added to a solution containing a beta-keto ester (IV). The mixture is reacted at a temperature in the range of from about 0xc2x0 to 60xc2x0 C. to yield the enamine compound (II).
An alkylene compound of formula (III) may be prepared according to procedures known to those skilled in the art. Scheme 3 illustrates one embodiment of the preparation process. 
A carbonyl compound of formula (V) may be subjected to a coupling reaction with an aldehyde compound of formula (VI) to give the alkylene compound of formula (III) according to a known procedure. For example, a compound of formula (V) wherein R6xe2x80x94Yxe2x80x94 is an optionally substituted heterocyclic-(CH2)2xe2x80x94 may be reacted with a compound of formula (VI) according to a procedure reported by L. Tietze et al. Liebigs Ann. Chem., pp. 321-329, 1988. This reaction may be carried out in a suitable reaction inert-solvent for example an aromatic hydrocarbon such as benzene, toluene and xylene, an alcohol such as methanol, ethanol, propanol and butanol, an ether such as diethyl ether, dioxane and tetrahydrofuran (THF), a halogenated hydrocarbon such as methylene dichloride, chloroform and dichloroethane, an amide such as N,N-dimethylformamide, and a nitrile such as acetonitrile. This reaction may be carried out at a temperature in the range of from about 0xc2x0 C. to the reflux temperature of the reaction mixture, preferably from about 80xc2x0 to the 120xc2x0 C. for from about 30 minutes to 24 hours, preferably from 30 minutes to 6 hours. This reaction may conveniently be carried in the presence of a base or acid catalyst. Suitable base catalysts are such as piperidine, pyridine and alkoxide, and suitable acid catalysts are such as acetic acid, TiCl4 and p-toluenesulfonic acid.
An intermediate compound of formula (V) may be prepared starting from a known compound according to a procedure known to those skilled in the art. For example, a compound of formula (V) wherein R6 is an optionally substituted heterocyclic (including heteroaryl) defined as above, and R3 is (C1-C1)alkoxy-C(xe2x95x90O)xe2x80x94 may be prepared according to the procedure described in Scheme 4. 
An aldehyde compound (VII), wherein R6 is defined as above, is reacted with malonic acid under a basic condition. For example, this reaction may be carried out in the presence of a weak base such as piperidine in a reaction inert solvent such as pyridine to give a carboxylic acid compound of formula (VIII). The compound (VIII) thus obtained may be subjected to an aliphatic nucleophilic substitution reaction in the presence of a coupling agent to give a pentenoate compound of formula (IX). This reaction may conveniently be carried out first by treating the compound of formula (VII) with a coupling agent such as N,Nxe2x80x2-carbonyldiimidazole in a reaction inert solvent such as dimethylformamide, then reacting with a neucleophilic reagent such as CH3O2CCH2K in the presence of a Lewis acid such as magnesium chloride. The former treatment may be carried out at a temperature in the range of from about 0xc2x0 to 60xc2x0 C. preferably at about room temperature for from about 1 minutes to 12 hours. The latter reaction may be carried out at the temperature in the range of from about 0xc2x0 to 100xc2x0 C., preferably from about room temperature to 60xc2x0 C. for from about 1 minutes to 12 hours. The compound of formula (IX) may be reduced over a metal catalyst under hydrogen atmosphere to give the compound of formula (V) according to a known procedure. Suitable catalysts are such as Raney nickel catalyst and a noble metal catalysts including palladium on carbon and palladium hydroxide. This reaction may be carried out in a reaction inert solvent such as methanol, at about room temperature under hydrogen at an appropriate pressure for example using a balloon, for about 1 minutes to 12 hours.
A ketone compound of formula (V) and a substituted benzaldehyde compound of formula (VI) may also be prepared according to known procedures (e.g., (1) D. Scherling, J. Labelled Compds. Radiopharm., Vol. 27, pp. 599-, 1989, (2) C. R. Holmquist et al., J. Org. Chem., Vol. 54, pp. 3528-, 1989, (3) S. N. Huckin et al., J. Am. Chem. Soc., Vol. 96, pp. 1082-, 1974, (4) J. C. S. Perkin I, pp. 529-, 1979, (5) Synthesis pp. 37, 1986, and (6) J. C. S. Chem. Commun., pp. 932-, 1977).
Compounds of formula (I) have a chiral center, and, if required, an enantiomeric mixture of the compounds may be separated by procedures known to those skilled in the art (e.g., using H.P.L.C. or fractional crystallization). Also, an enantiomeric mixture of compounds of formula (III) may be optically separated by the similar methods prior to being subjected to the preparation processes of this invention.
Compounds of formula (I) prepared according to the procedures described as above may be isolated and purified by conventional procedures such as recrystallization or chlomatographic purification.
Compounds of formula (I) thus obtained may further be subjected to desired reactions. For example, the compounds wherein R2 is xe2x80x94COOH, may be subjected to coupling reactions with a desired amine or imine compounds to give such compounds as disclosed in WO 96/06082, WO 97/30048, U.S. Pat. No. 5,861,402 or the like.
With the processes of the present invention, 1,4-dihydropyridine compounds can be effectively prepared under mild conditions. Especially, 1,4-dihydropyridine compunds which are difficult to be synthesized by Hantzsch method (not under mild conditions), can be synthesized because of the mild conditions in the present invention.